Ablation of EWS-FLI1 by USP9X inhibition suppresses cancer cell growth in Ewing sarcoma

被引：9

作者：

Wang, Shan ^{[1
,2
]}

Huo, Xiaofang ^{[2
]}

Yang, Yiping ^{[1
]}

Mo, Yingxi ^{[1
]}

Kollipara, Rahul K. ^{[2
]}

Kittler, Ralf ^{[2
,3
,4
,5
,6
]}

机构：

[1] Guangxi Med Univ, Dept Res, Canc Hosp, Nanning, Guangxi Zhuang, Peoples R China

[2] Univ Texas Southwestern Med Ctr, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX USA

[3] Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX USA

[5] Univ Texas Southwestern Med Ctr Dallas, Green Ctr Reprod Biol Sci, Dallas, TX USA

[6] UT Southwestern Med Ctr, McDermott Ctr Human Growth & Dev, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

来源：

CANCER LETTERS | 2023年 / 552卷

关键词：

Ewing sarcoma; USP9X; EWS-FLI1; Ubiquitination; WP1130; SHORT INTERFERING RNAS; EWS/FLI-1; PHENOTYPE; SURVIVAL; THERAPY; PROGRAM; FUSION;

D O I：

10.1016/j.canlet.2022.215984

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The neomorphic transcription factor EWS-FLI1 is a key driver of Ewing sarcoma. Ablation of EWS-FLI1 may present a promising therapeutic strategy for this malignancy. Here we found that the deubiquitinase, ubiquitin specific peptidase 9 X-linked (USP9X) stabilizes EWS-FLI1 protein expression in Ewing sarcoma. We show that USP9X binds the ETS domain of EWS-FLI1 in Ewing sarcoma cells and deubiquitinates EWS-FLI1 and that USP9X and EWS-FLI1 protein expression is correlated in clinical Ewing sarcoma specimens. We found that treatment of Ewing sarcoma cells with the USP9X inhibitor WP1130 mediates rapid EWS-FLI1 degradation in vitro and in vivo which coincides with reduced growth of Ewing sarcoma cells and tumors. Our results suggest that USP9X might be a potential therapeutic target to mediate EWS-FLI1 depletion in Ewing sarcoma.

引用

页数：8

共 50 条

[41] EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism [J].

Olmedo-Pelayo, Joaquin ;

Granado-Calle, Esperanza ;

Delgado-Bellido, Daniel ;

Lobo-Selma, Laura ;

Jordan-Perez, Carmen ;

Monteiro-Amaral, Ana T. ;

Ehlers, Anna C. ;

Ohmura, Shunya ;

Garcia-Dominguez, Daniel J. ;

Mackintosh, Carlos ;

Carcaboso, Angel M. ;

Alonso, Javier ;

Machado, Isidro ;

Llombart-Bosch, Antonio ;

Scotlandi, Katia ;

Gruenewald, Thomas G. P. ;

Gomez-Herreros, Fernando ;

de Alava, Enrique .

ONCOGENE, 2025,

[42] EWS-FLI-1-Targeted Cytotoxic T-cell Killing of Multiple Tumor Types Belonging to the Ewing Sarcoma Family of Tumors [J].

Evans, Christopher H. ;

Liu, Fangjun ;

Porter, Ryan M. ;

O'Sullivan, Regina P. ;

Merghoub, Taha ;

Lunsford, Elaine P. ;

Robichaud, Kyle ;

Van Valen, Frans ;

Lessnick, Stephen L. ;

Gebhardt, Mark C. ;

Wells, James W. .

CLINICAL CANCER RESEARCH, 2012, 18 (19) :5341-5351

[43] Small interfering RNAs expressed from a pol III promoter suppress the EWS/Fli-1 transcript in an Ewing sarcoma cell line [J].

Dohjima, T ;

Lee, NS ;

Li, HT ;

Ohno, T ;

Rossi, JJ .

MOLECULAR THERAPY, 2003, 7 (06) :811-816

[44] The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition [J].

Chander Peddaboina ;

Daniel Jupiter ;

Steven Fletcher ;

Jeremy L Yap ;

Arun Rai ;

Richard P Tobin ;

Weihua Jiang ;

Philip Rascoe ;

M Karen Newell Rogers ;

W Roy Smythe ;

Xiaobo Cao .

BMC Cancer, 12

[45] Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis [J].

Sun, Hanshi ;

Kapuria, Vaibhav ;

Peterson, Luke F. ;

Fang, Dexing ;

Bornmann, William G. ;

Bartholomeusz, Geoffrey ;

Talpaz, Moshe ;

Donato, Nicholas J. .

BLOOD, 2011, 117 (11) :3151-3162

[46] Deubiquitinase USP9x regulates the proline biosynthesis pathway in non-small cell lung cancer [J].

Becirovic, Tina ;

Zhang, Boxi ;

Lindskog, Cecilia ;

Norberg, Erik ;

Vakifahmetoglu-Norberg, Helin ;

Kaminskyy, Vitaliy O. ;

Kochetkova, Elena .

CELL DEATH DISCOVERY, 2024, 10 (01)

[47] EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells [J].

Riggi, Nicolo ;

Suva, Mario-Luca ;

De Vito, Claudio ;

Provero, Paolo ;

Stehle, Jean-Christophe ;

Baumer, Karine ;

Cironi, Luisa ;

Janiszewska, Michalina ;

Petricevic, Tanja ;

Suva, Domizio ;

Tercier, Stephane ;

Joseph, Jean-Marc ;

Guillou, Louis ;

Stamenkovic, Ivan .

GENES & DEVELOPMENT, 2010, 24 (09) :916-932

[48] Elevated expression of USP9X correlates with poor prognosis in human non-small cell lung cancer [J].

Wang, You ;

Liu, Yu ;

Yang, Bo ;

Cao, Hong ;

Yang, Chun-Xu ;

Ouyang, Wen ;

Zhang, Shi-Min ;

Yang, Gui-Fang ;

Zhou, Fu-Xiang ;

Zhou, Yun-Feng ;

Xie, Cong-Hua .

JOURNAL OF THORACIC DISEASE, 2015, 7 (04) :672-+

[49] Stable interference of EWS–FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target [J].

D Herrero-Martín ;

D Osuna ;

J L Ordóñez ;

V Sevillano ;

A S Martins ;

C Mackintosh ;

M Campos ;

J Madoz-Gúrpide ;

A P Otero-Motta ;

G Caballero ;

A T Amaral ;

D H Wai ;

Y Braun ;

M Eisenacher ;

K-L Schaefer ;

C Poremba ;

E de Alava .

British Journal of Cancer, 2009, 101 :80-90

[50] USP9x promotes CD8+ T-cell dysfunction in association with autophagy inhibition in septic liver injury [J].

Sheng, Lulu ;

Chen, Juntao ;

Tong, Yiqing ;

Zhang, Yi ;

Feng, Qiming ;

Tang, Zhenghao .

ACTA BIOCHIMICA ET BIOPHYSICA SINICA, 2022, 54 (12) :1765-1774

← 1 2 3 4 5 →